The long-term objective of this research project is to unveil the molecular and cellular mechanisms by which different forms of the platelet-derived growth factor (PDGF) regulate a diverse array of cellular processes including cell proliferation, migration, transformation and apoptosis. PDGF exerts its cellular effects by activating two structurally related cell surface receptor tyrosine kinases (a-PDGFR and beta-PDGFR). Although a number of signaling molecules activated by these receptors have been identified, little is known about which signaling pathways are a- or beta-PDGFR-specific, and how these signals are integrated to agonize or antagonize specific cellular processes. During the last funding period, we have investigated a- and beta-PDGFR-specific signaling pathways critical for PDGF-specific cellular processes. We have found that a-PDGFR antagonizes beta-PDGFR-mediated transformation through JNK-1 activation, while both a- and beta-receptors effectively activate ERKs and trigger the cell cycle. These results revealed a striking feature of PDGF signaling: that the specificity and the strength of the PDGF-growth signal is modulated by a-PDGFR-mediated simultaneous activation of stimulatory and inhibitory signals, whereas beta-PDGFR mainly induces a stimulatory signal. The preliminary studies show that a-PDGFR is required for cell cycle arrest at G1, and that a-PDGFR-activated iNK-i induces p21 WAF 1/CIP1 (an inhibitor of cell cycle) expression and enhances caspase (an initiator of apoptosis) activation, providing a mechanistic insight for a-PDGFR-mediated growth inhibitory signals. Based on these observations, we hypothesize that a-PDGFR signaling is critical for PDGF regulation of apoptosis and cell cycle checkpoint, and that JNK-1 is an essential component for the a-PDGFR mediated negative signal. To test our hypothesis, we propose (1) to investigate the molecular mechanism by which aPDGFR, but not beta-PDGFR, activates JNK-1; (2) to investigate a-PDGFR- and beta-PDGFR-specific cell cycle regulation; (3) to investigate the molecular mechanisms by which JNK-1 regulates apoptosis; and (4) to further investigate the a-PDGFR signaling pathways induced by different PDGF isoforms in normal and tumor cells. The accomplishment of these aims will help in unveiling the molecular and cellular mechanisms governing the specificity of growth factor signaling, and greatly contribute to the collective endeavor to understand the role of PDGF signaling in physiological and pathological conditions.